A. Rheumatologic Diseases Overview [10]

1. Rheumatologic Syndrome Characteristics
   1. Idiopathic production of autoantibodies (AutoAbs) and/or
   2. Idiopathic production of immune complexes and/or
   3. Abnormal cellular immune mechanisms
   4. Rule out other causes of autoantibodies / immune complexes (such as endocarditis)
2. Most involve both B and T lymphocyte dysfunction [10]
   1. Genetic susceptibility underlies disease in most patients
   2. Inappropropriate activation of specific immune cells is likely trigger
   3. Antigenic (self-antigen) stimulation of low-level self-reactive lymphocytes
   4. Overexuberant production of inflammatory cytokines is likely required
   5. Epitope spreading occurs: increase in number of autoantigens targeted by T cells and antibodies during the course of disease
3. Course of Disease
   1. May alter over time
   2. Individual cases may change as regards their classification and management
4. Clinical Classification
   1. Most useful classifications clinical with laboratory data
   2. Clinical (history/physical) description is main diagnostic tool, couple with testing
   3. Detection of various specific autoantibodies (auto-Abs) is often helpful
   4. Rheumatologic syndromes may be best thought of as a continuum of related diseases

B. Autoantibodies [12]

1. Most common are antibodies which stain cell nuclei
2. These are "anti-nuclear antibodies" (ANA)
3. Specific autoantibody tests have been developed, making pattern of ANA less important
4. Pathogenesis of Autoatnibodies Unclear
   1. T lymphocytes are most likely needed to help B cells produce autoantibodies [8]
   2. Failure of tolerance mechanisms at T and B cell levels responsible for autoantibodies [9]
5. ANA and SLE [1,3]
   1. Sensitivity of ANA for SLE is >95%
   2. Positive predictive value (PPV) is usually low (<20%) due to low prevalence of disease
   3. ANA become positive a mean of 3.3 years (up to 9.4) prior to onset of SLE
   4. At least one SLE autoantibody tested positive before diagnosis in 88% of patients
6. Overall Utility of ANA Testing [1]
   1. Specificity for SLE ~85% and is similar for all rheumatogic diseases
   2. Utility of test is lower in an older population where SLE is less common
   3. For general population at risk for SLE, 3.8% of non-SLE persons positive for ANA [3]
7. Autoantibodies [2,12]

   Autoantibodies: Percent of Positive Patients in Each Disease Category
   Pattern/Disease	SLE*	MCTD	PSS	CREST	SS	RA	Normal
   Anti-Nuclear Abs	95	>95	80	75	70	25	5
   Anti-dsDNA	70	-	-	-	-	-	-
   Anti-Sm	20	-	-	-	-	-	-
   Anti-Ro (SS-A)	30	5	5	-	70	5	<5
   Anti-La (SS-B)	15	5	5	-	60	5	<5
   Anti-Nucleolar	80	-	80	-	80	5	-
   Anti-Histone	60	-	-	-	-	20	5
   Anti-RNP	30	>95	80	-	5	5	-
   Anti-Centromere	5	5	10	60	-	-	-
   Anti-Topo I	-	-	20	-	-	-	-
   Rheumatoid Factor	5	-	-	-	5	80	<5
   Anticardiolipin [4]	15	-	7	7	7	15	5
   Antiendothelial [5]	~10	~10	80	45	-	-	-
   *SLE = Systemic Lupus Erythematosus
   MCTD = Mixed Connective Tissue Disease
   PSS = Progressive (diffuse) Systemic Sclerosis
   CREST = Localized Scleroderma
   SS = Sjogren Syndrome
   RA = Rheumatoid Arthritis

C. Antinuclear Antibody Staining Patterns [7,12]

1. Peripheral
   1. Double Stranded DNA: SLE - especially with glomerulonephritis
   2. Single Stranded DNA: Nonspecific (10-15% of normal persons)
   3. May be specific for other polyanions (such as heparin) and bind DNA as a cross-reaction
2. Homogeneous
   1. DNA-Histone Complex: SLE, Drug induced LE, lupus nephritis [11]
   2. Antihistone Antibody alone suggests drug-induced Lupus
3. Speckled Pattern
   1. Sm (Smith) complexed with U1-U6: SLE - especially with Renal, CNS Disease
   2. Ribonucleoprotein (RNP): SLE, SS, Scleroderma, Polymyositis, MCTD
   3. Ro (Robert) Antigen (SS-A)
   4. Subacute cutaneous LE, SLE, SS, Photosensitive skin disease
      1. Keratoconjunctivitis, Neonatal LE
   5. La (SS-B) Antigen: SS, SLE - especially with Keratoconjunctivitis sicca
   6. Jo-1 (histidyl-tRNA synthetase): Polymyositis, especially with pulmonary disease
   7. Anti-DNA Topo I (Scl70): Diffuse Scleroderma (highly specific) [6]
4. Centromere Pattern [6]
   1. Limited Systemic Sclerosis - CREST Syndrome
   2. Highly specific for this form of scleroderma
5. Nucleolar Pattern
   1. RNA Polymerase 1: PM-Sc1: Scleroderma, MCTD, Polymyositis
6. Cytoplasmic Pattern
   1. Anti-mitochondrial: Primary Biliarly Cirrhosis
   2. Anti-smooth muscle: Autoimmune hepatitis, Primary Biliary Cirrhosis

D. Other Causes of Positive ANA

1. Normal persons (especially women, especially titer <1:160)
2. Primary Biliary Cirrhosis
3. Autoimmune Thyroiditis
4. Viral Infection - especially EBV
5. Autoimmune Hepatitis
6. Multiple Sclerosis (low titer)
7. Overlap syndromes (see above)
8. Drug - usually as drug induced lupus syndromes including procainamide, phenytoin

E. Differential of Positive Rheumatoid Factor

1. Bacterial (usually chronic)
   1. Subacute Bacterial Endocarditis (SBE)
   2. Tuberculosis, ? Atypical Mycobacterial infections, Leprosy
   3. Spirochetes: Lyme Disease, Syphilis
2. Viral
   1. Rubella
   2. EBV (mononucleosis)
   3. CMV
   4. Influenza
3. Chronic Inflammatory Disease
   1. Rheumatoid Arthritis
   2. Systemic Lupus Erythematosus (SLE)
   3. Sjogren's Syndrome
   4. Sarcoidosis
   5. Chronic Inflammatory Liver Disease
   6. Interstitial Lung Disease
   7. Periodontal Disease
4. Cryoglobulinemia
   1. Type III - mixed polyclonal rheumatoid factor
   2. Type II most commonly (RF + mixed gammopathy)
   3. Type I - monoclonal rheumatoid factor alone
5. Hypergammaglobulonemic Purpura

References

1. Slater CA, Davis RB, Shmerling RH. 1996. Arch Intern Med. 156(13):1421
2. von Muhlen CA, and Tan EM. 1995. Semin Arthritis Rheumat. 24(5):323
3. Arbuckle MR, McClain MT, Rubertone MV, et al. 2003. NEJM. 349(16):1526
4. Merkel PA, Chang Y, Pierangeli SS, et al. 1996. Am J Med. 101(6):576
5. Salojin KV, Le Tonqueze M, Saraux A, et al. 1997. Am J Med. 102(2):178
6. Spencer-Green G, Alter D, Welch HG. 1997. Am J Med. 103(3):242
7. Hahn BH. 1998. NEJM. 338(19):1359
8. Albert LJ and Inman RD. 1999. NEJM. 341(27):2068
9. Kamradt T and Mitchison NA. 2001. NEJM. 344(9):655
10. Davidson A and Diamond B. 2001. NEJM. 345(5):340
11. Cortes-Hernandez J, Ordi-Ros J, Labrador M, et al. 2004. Am J Med. 116(3):165
12. Rahman A and Isenberg DA. 2008. NEJM. 358(9):929